Faculty Bibliography

Intracerebral hemorrhage (ICH) accounts for 10% to 15% of all strokes and is a major cause of morbidity and mortality. Despite advances in management, numerous clinical trials have failed to demonstrate significant benefit of medical and surgical interventions, underscoring the need for the identification of novel therapeutic targets based on improved understanding of ICH pathophysiology and optimal risk stratification based on reliable and effective prognosticators. The alternative complement cascade has been implicated as an important contributor to neurological injury after ICH. Therefore, common, functionally relevant genetic variants in the key components of this pathway have been associated with greater inflammation post-ictus, further cerebral damage, and ultimately, a worse outcome. We investigated the affects of single-nucleotide polymorphisms (SNP) on mortality in complement component 3 C3 (rs2230199), complement component 5 C5 (rs17611), and Complement Factor H (CFH; rs1061170) genes, which are associated with the onset and progression of several neurological diseases, in a prospective cohort of patients with spontaneous ICH. From February 2009 through May 2010, adult patients with spontaneous ICH were admitted to the Columbia University Neurological Intensive Care Unit and enrolled in the Intracerebral Hemorrhage Outcomes Project. Demographic, clinical, radiographic, and treatment data were prospectively collected. Buccal swabs were obtained, and isolated cells were sequenced for the aforementioned SNP. A total of 103 patients were admitted with ICH, and of these, 82 consented for genetic testing and were included in the analysis. The median age was 61 years and 39% were females. The median Glasgow Coma Scale score on admission was 11.5. The CFH SNP was significantly associated with both discharge (p = 0.01) and 6-month mortality (p = 0.02), while no such association was observed for C3 (p = 0.545 and p = 0.830) or C5 (p = 0.983 and p = 0.536) SNP. Additionally, after controlling for pertinent variables identified in the univariate analysis, the CFH genotype independently predicted mortality at discharge (p = 0.019, odds ratio [OR] 7.62, 95% confidence interval [CI] 1.40-41.6) and at 6 months (p = 0.041, OR 1.822, 95% CI 1.025-3.239). The CFH genotype was also independently predictive of survival duration (p = 0.041, OR 1.822, 95% CI 1.025-3.239). We concluded that CFH Y402H polymorphism independently predicts mortality at discharge and 6-months and survival duration after spontaneous ICH.

Traumatic brain injury (TBI) is the current leading cause of death in children over 1 year of age. Adequate management and care of pediatric patients is critical to ensure the best functional outcome in this population. In their controversial trial, Cooper et al. concluded that decompressive craniectomy following TBI did not improve clinical outcome of the analyzed adult population. While the study did not target pediatric populations, the results do raise important and timely clinical questions regarding the effectiveness of decompressive surgery in pediatric patients. There is still a paucity of evidence regarding the effectiveness of this therapy in a pediatric population, and there is an especially noticeable knowledge gap surrounding age-stratified interventions in pediatric trauma. The purposes of this review are to first explore the anatomical variations between pediatric and adult populations in the setting of TBI. Second, the authors assess how these differences between adult and pediatric populations could translate into differences in the impact of decompressive surgery following TBI.

The role of the complement cascade in the pathophysiology of cerebral arteriovenous malformation (AVM) is largely undefined. Complement subcomponents, C3a and C5a, are potent anaphylatoxins and key mediators of immuno-inflammatory response. Complement activation may contribute to the pro-inflammatory state observed in AVM. Thus, we sought to determine the systemic levels of C3a and C5a and their response to treatments in patients with AVM. Blood samples of 18 patients undergoing treatment for unruptured AVM, and from 30 healthy control participants, were obtained at four times: (i) pre-treatment, (ii) 24-hours post-embolization, (iii) 24-hours post-resection, and at 1-month follow-up. Plasma concentrations of C3a and C5a were measured using enzyme-linked immunosorbent assay. The pre-treatment mean plasma C3a level was significantly higher in patients with AVM (1817±168 ng/mL) compared to controls (1126±151 ng/mL). The mean C3a level decreased 24-hours after embolization (1482±170 ng/mL) and remained at statistically similar levels 24-hours after resection (1511±149 ng/mL) and at 1-month follow-up (1535±133 ng/mL). Mean C3a levels at the three time points were higher than control levels.The baseline mean plasma C5a level was significantly elevated in patients with AVM (13.1±2.2 ng/mL) compared to controls (3.9±1.5 ng/mL).Mean C5a level decreasedpost-embolization (8.2±2.3 ng/mL) and remained at similar levels post-resection (8.5±3.0 ng/mL) and at 1-month follow-up (7.7±2.9 ng/mL). Mean C5a levels at the three time points were significantly higher than the control levels. We conclude that systemic C3a and C5a levels in patients with AVM are elevated at baseline, decrease significantly after embolization, and remain at the new baseline levels after surgery and 1-month follow-up.

BACKGROUND AND PURPOSE/OBJECTIVE:Hyperglycemia after spontaneous intracerebral hemorrhage (ICH) is associated with poor outcome, but the pathophysiology of ICH-induced glucose dysregulation remains unclear. We sought to identify clinical and radiographic parameters of ICH that are associated with admission hyperglycemia. METHODS:Patients admitted to the Columbia University Medical Center Neurological Intensive Care Unit with spontaneous ICH between January 2009 and September 2010 were prospectively enrolled in the ICH Outcomes Project. Clinical, radiographic, and laboratory data were collected prospectively. Receiver operating characteristic analysis was used to identify the glucose level with optimal sensitivity and specificity for in-hospital mortality. Logistic and linear regression analyses were used to identify independent predictors of outcome measures where appropriate. RESULTS:One hundred four patients admitted during the study period were included in the analysis. Mean admission glucose level was 8.23 ± 3.15 mmol/L (3.83 to 18.89 mmol/L) and 23.2% had a history of diabetes mellitus. Admission glucose was significantly associated with discharge (P=0.003) and 3-month mortality (P=0.002). Critical hyperglycemia defined at 10 mmol/L independently predicted discharge mortality (P=0.027; OR, 4.381; 95% CI, 1.186 to 16.174) and 3-month mortality (P=0.011; OR, 10.95; 95% CI, 1.886 to 62.41). Admission intraventricular extension score (P=0.038; OR, 1.117; 95% CI, 1.043 to 1.197) and diabetes mellitus (P=0.002; OR, 5.530; 95% CI, 1.833 to 16.689) were independent predictors of critical hyperglycemia. The intraventricular extension score (B=0.115, P=0.001) linearly correlated with admission glucose level (R=0.612, P=0.001) after adjusting for other clinical variables. CONCLUSIONS:Admission hyperglycemia after spontaneous ICH is associated with poor outcome and potentially related to the presence and severity of intraventricular extension.

Outcome after intraarterial therapy (IAT) for acute ischemic stroke remains variable, suggesting that improved patient selection is needed to better identify patients likely to benefit from treatment. The authors evaluate the predictive accuracies of the Houston IAT (HIAT) and the Totaled Health Risks in Vascular Events (THRIVE) scores in an independent cohort and review the existing literature detailing additional predictive factors to be used in patient selection for IAT. They reviewed their center's endovascular records from January 2004 to July 2010 and identified patients who had acute ischemic stroke and underwent IAT. They calculated individual HIAT and THRIVE scores using patient age, admission National Institutes of Health Stroke Scale (NIHSS) score, admission glucose level, and medical history. The scores' predictive accuracies for good outcome (discharge modified Rankin Scale score ≤ 3) were analyzed using receiver operating characteristics analysis. The THRIVE score predicts poor outcome after IAT with reasonable accuracy and may perform better than the HIAT score. Nevertheless, both measures may have significant clinical utility; further validation in larger cohorts that accounts for differences in patient demographic characteristics, variation in time-to-treatment, and center preferences with respect to IAT modalities is needed. Additional patient predictive factors have been reported but not yet incorporated into predictive scales; the authors suggest the need for additional data analysis to determine the independent predictive value of patient admission NIHSS score, age, admission hyperglycemia, patient comorbidities, thrombus burden, collateral flow, time to treatment, and baseline neuroimaging findings.

Intracerebral hemorrhage (ICH) is associated with higher mortality and morbidity than any other form of stroke. However, there currently are no treatments proven to improve outcomes after ICH, and therefore, new effective therapies are urgently needed. Growing insight into ICH pathophysiology has led to the development of neuroprotective strategies that aim to improve the outcome through reduction of secondary pathologic processes. Many neuroprotectants target molecules or pathways involved in hematoma degradation, inflammation or apoptosis, and have demonstrated potential clinical benefits in experimental settings. We extensively reviewed the current understanding of ICH pathophysiology as well as promising experimental neuroprotective agents with particular focus on their mechanisms of action. Continued advances in ICH knowledge, increased understanding of neuroprotective mechanisms, and improvement in the ability to modulate molecular and pathologic events with multitargeting agents will lead to successful clinical trials and bench-to-bedside translation of neuroprotective strategies.

INTRODUCTION/BACKGROUND:Exposure to isoflurane gas prior to neurological injury, known as anesthetic preconditioning, has been shown to provide neuroprotective benefits in animal models of ischemic stroke. Given the common mediators of cellular injury in ischemic and hemorrhagic stroke, we hypothesize that isoflurane preconditioning will provide neurological protection in intracerebral hemorrhage (ICH). METHODS:24 h prior to intracerebral hemorrhage, C57BL/6J mice were preconditioned with a 4-h exposure to 1% isoflurane gas or room air. Intracerebral hemorrhage was performed using a double infusion of 30-μL autologous whole blood. Neurological function was evaluated at 24, 48 and 72 h using the 28-point test. Mice were sacrificed at 72 h, and brain edema was measured. RESULTS:Mice preconditioned with isoflurane performed better than control mice on 28-point testing at 24 h, but not at 48 or 72 h. There was no significant difference in ipsilateral hemispheric edema between mice preconditioned with isoflurane and control mice. CONCLUSION/CONCLUSIONS:These results demonstrate the early functional neuroprotective effects of anesthetic preconditioning in ICH and suggest that methods of preconditioning that afford protection in ischemia may also provide protection in ICH.

In this report, the evidence, mechanisms, and rationale for the practice of artificial cranial deformation (ACD) in ancient Peru and during Akhenaten's reign in the 18th dynasty in Egypt (1375-1358 BCE) are reviewed. The authors argue that insufficient attention has been given to the sociopolitical implications of the practice in both regions. While evidence from ancient Peru is widespread and complex, there are comparatively fewer examples of deformed crania from the period of Akhenaten's rule. Nevertheless, Akhenaten's own deformity, the skull of the so-called "Younger Lady" mummy, and Tutankhamen's skull all evince some degree of plagiocephaly, suggesting the need for further research using evidence from depictions of the royal family in reliefs and busts. Following the anthropological review, a neurosurgical focus is directed to instances of plagiocephaly in modern medicine, with special attention to the conditions' etiology, consequences, and treatment. Novel clinical studies on varying modes of treatment will also be studied, together forming a comprehensive review of ACD, both in the past and present.

External ventricular drain (EVD) placement is standard of care in the management of aneurysmal subarachnoid haemorrhage-associated hydrocephalus (aSAH). However, there are no guidelines for EVD placement and management after aSAH. Optimal EVD insertion conditions, techniques to reduce the risk of EVD-associated infection and aneurysmal rebleeding, and methods of EVD removal are critical, yet incompletely answered management variables. The present literature consists primarily of small studies with heterogeneous populations and variable outcome measures, and suggests the following: EVDs may increase the risk of rebleeding; EVDs are increasingly placed by non-neurosurgeons with unclear results; intraparenchymal ICP monitors may be safely considered (with or without spinal drainage) in the setting of difficult EVD placement; the optimal timing and manner of EVD removal has yet to be defined; and the efficacy of prophylactic systemic antibiotics and antibiotic-coated EVDs needs further investigation. Nevertheless, there are no definitive practice guidelines for EVD placement and management techniques in aSAH patients. Large prospective randomised trials are needed to definitively address important gaps in our understanding of EVD management principles in the neurocritical care setting.

BACKGROUND:Delayed ischemic neurological deficits (DIND) due to cerebral vasospasm remains a major cause of morbidity and mortality following aneurysmal subarachnoid hemorrhage (aSAH). Methods to prevent DIND remain limited both in safety and efficacy. A novel intra-aortic dual balloon catheter (NeuroFloâ„¢: CoAxia, Maple Grove, MN) is under investigation for treatment of ischemic stroke, including DIND. Because this technique does not require cerebral artery navigation, it may be useful as a bedside procedure, outside of the conventional angiography suite. We report the first case of ultrasound-guided application of the NeuroFloâ„¢ system at bedside in the Neurological Intensive Care Unit. METHODS:A 52-year-old woman presented with Hunt Hess IV aSAH complicated by medically refractory cerebral vasospasm. Despite surgical clipping of her aneurysm, the patient remained critically ill, failing maximal conventional medical therapy. For that reason, the NeuroFloâ„¢ system was deployed using two-dimensional, spectral and color-flow Doppler ultrasound guidance at the patient's bedside while maintaining all forms of cerebral blood flow monitoring. RESULTS:The procedure was well tolerated and there was no complication. CONCLUSION/CONCLUSIONS:Bedside application of the NeuroFloâ„¢ system may be safely performed in critically ill patients. The NeuroFloâ„¢ system is under investigation for treatment of refractory cerebral vasospasm to prevent delayed ischemic neurological disease.